ONCOLOGY DRUGS:THE JOURNEY FROM

MANUFACTURER

TO END USER

Dr. SALMAH BAHRI

Director of Pharmacy Enforcement

Pharmaceutical Services Division

Ministry of Health Malaysia

INTRODUCTION

• Health is a fundamental human right. Access tomedicines is a fundamental element of the right tohealth.

• Key issues related to access to medicines include :availability and affordability; sustainable financing; priceand quality control; efficacy and effectiveness ofmedicines; procurement practices and procedures,supply chains.

• By law, before a medicine can be placed on the market,it must be given a marketing authorisation (productlicence) by a medicines regulator

• FIRST STEP in ensuring AVAILABILITY of the medicine:Marketing authorisation (via product registration) in thecountry

FROM DRUG DEVELOPMENT TO

MARKETING

During the lifecycle of a new medicine, there are considerable

hurdles to overcome before the medicine successfully reaches

the market.

REGULATORY SYSTEM IN MALAYSIA

• Control of Drugs and Cosmetics Regulations (CDCR)

1984 - Legal framework and empowers the Drug

Control Authority (DCA) to implement drug registration.

• Under the CDCR 1984, Regulation 7(1): Except as

otherwise provided in these Regulations, no person shall

manufacture, sell, supply, import, possess or administer

any product unless:

(a) the product is a registered product; and

(b) the person holds the appropriate licence required and

issued under these Regulations.

• National Pharmaceutical Control Bureau (NPCB) set

up in 1978, currently serves as the Secretariat to DCA

OBJECTIVE OF REGISTRATION

Protect the health of our public by

ensuring safety, efficacy and

quality of pharmaceutical

products marketed in Malaysia

WHY REGISTRATION IS IMPORTANT?

The registration system is designed to:

• guarantee that all those involved are answerable for their actions;

• ensure that processes, supplies, and quality can bethoroughly monitored;

• enable swift corrective action to be taken when needed.

• It is not influenced by the cost effectiveness or value formoney of a medicine;

• License will be granted a medicine meets high standardsof safety and quality, and that it works for the purposeintended. This is denoted by a product licence ormarketing authorisation number (MAL.....)

REQUIREMENTS FOR REGISTRATION

7

National Pharmaceutical Control Bureau

Part I

Common Administrative

Data

& Product Information

(for all category of products)

Part II

Quality

(for all category of

products)

Part III

Non-clinical

(for innovator, new

chemical entity &

biotechnology products

Part IV

Clinical

(for innovator, new

chemical entity &

biotechnology products

ACTD

Country specific,

administrative data, not

part of

ACTD

Registration requirements based on ASEAN Common Technical Dossiers ACTD,

adopted from ICH CTD, has been implemented in Malaysia since July 2003.

PRODUCT REGISTRATION CRITERIA

Products Particulars Product Formula

Labeling Requirement

Interchangeability

Manufacturer-GMP

-CPP

-CFS

Compulsory

labeling

requirement

Additional

Warning/

Precaution

Product Name

Product Description

Pack size

Type of container

Bioequivalence

/Bioavailability

Studies

Banned ingredient

Limits,

Product testing,

FPQC, Stability

(QUALITY, SAFETY, EFFICACY)

Product Evaluation Committee

(within NPCB) /Mesyuarat JKPP

Verification of GMP status (approval from recognised authority

of the country of origin), CPP

Protocol Evaluation (NCE & Generic Rx & OTC) and Sample

Testing (Traditional)

Drug Control Authority

(DCA)/ Mesyuarat PBKD(decision making body

-meets monthly)

NCE & Biotech products – sent to panel of experts for comments.

RegisteredIssue MAL no.

Application rejected

Applicant can appeal through

Minister of Health for review of

DCA’s decision

Evaluation of application dossier

REGISTRATION PROCESS

POST REGISTRATION

• The NPCB continues to monitor safety, efficacy & quality

of products through pharmacovigilance

• Malaysian Adverse Drug Reactions Advisory Committee

(MADRAC) was established under Drug Control

Authority (DCA) to perform the function of

pharmacovigilance for drugs registered for use in

Malaysia.

• Health professionals & pharmaceutical companies carry

the responsibility to report ADR to MADRAC.

• ADR reporting form is accessible at

http://portal.bpfk.gov.my

POST REGISTRATION

• Post-registration, a medicine must be listed in MOH Drug

Formulary before it can be used in MOH facilities;

• MOH Drug Formulary objective -

To ensure only efficacious, safe and cost-effective drugs

are used in MOH institutions;

• In line with Malaysia National Medicines Policy’s

(MNMP) main aim: Towards achieving rational use of

safe, effective & affordable essential medicines

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MINISTRY OF HEALTH FORMULARY

Registered Products by

DCA

MOH Formulary

MOH Hospital

Formulary

MOH Primary

Care Formulary

July 2014

1642 items

• 828 chemical

entities

• Including 320

items in NEML

September 2014

Poison 7143

OTC 4185• Drugs approved

to be used in

MOH facilities

by Drug List

Review Panel

• Reviewed 3

times a year

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Governance in Medicines

Quality Use of Medicines

Partnership and Collaboration for the Healthcare Industry

Quality, Safety and Efficacy of

Medicines

Access to Medicines

MNMP II COMPONENTS

MOH DRUG FORMULARY

LISTING PROCESS

MNMP Strategy for Access to Medicines:

Selection of Medicines

A fair and transparent medicines selection mechanism

in accordance with the country’s health needs by

emphasising clinical effectiveness and cost-

effectiveness of treatments

Pharmaceutical Expenditure

Adapted from OECD/WHO (2012) 15

Pharmaceutical Expenditure

Global medicines spending has surpassed US

$1 trillion per year

Medicines spending accounts for up to 67% of

total health expenditures in some countries ,

mostly paid out of pocket by consumers.

Asian countries, pharmaceutical share of total

health spending range between 8% -50%

Malaysia, pharmaceutical expenditure is 8.8% of

total health expenditure

Source :Wagner et al. BMC Health Services Research 2014 ; OECD/ WHO (2012), “Pharmaceutical

expenditure” in Health at a Glance Asia Pacific 2012

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ACCESS & BUDGET CONSTRAINTS

1.76

Billion

1.98

Billion

2.2

Billion

2011 2012 2013

Medicine Expenditure as % of Total MOH Operating Budget (2012) = 11.4%

Source: Malaysia Health System Review 2013

There is a need to have balance between access and

affordability considering the budget constraints and

increasing trends in medicine in expenditure.

MOH medicines expenditure:

# Top 5 Principal Causes of Death

in the MOH, 2013

%

1 Diseases of the circulatory system 24.38

2 Diseases of the respiratory system 22.73

3 Certain infectious and parasitic

diseases

13.96

4 Neoplasms 12.12

5 Injury, poisoning and certain other

consequences of external causes

5.05

Burden of Disease

MOH EXPENDITURE ON ONCOLOGY

MEDICINES

YEAR

TOTAL

EXPENDITURE ON

ONCOLOGY

MEDICINES

PERCENTAGE

SPENT ON

ONCOLOGY

(FROM TOTAL

MEDICINES

EXPENDITURE)

2012 RM 167,224,314.66 8.4%

2013 RM 187,573,860.88 8.6%

FORMULARY

LISTING PROCESS Specialist/ FMS/

Medical Officer/

Pharmacists fill

proforma

Hospital/

Health Drug

Committees

State Drug

Committees

National Drug Formulary

Secretariat (PSD)

Technical Drug

Working CommitteeDrug Evaluation

(Pharmacoeconomic Unit,

PSD)

MOH Drug

List Review

Panel

Inform all States/ MOH

Institutions via circular

Request closed/ filed

List into local formulary

Proposer informed/

Request filed

Proposer informed/

Request filed

Approved

2 sets of proforma with

clinical references/ papers

Hospital/

State Drug

Committees

Appeal

Results

Feedbacks

FORMULARY LISTING PROCESS

Evaluation by Pharmacoeconomics Unit

Presentation to Drug List Review Panel

Dissemination of Results

Application received & screened by MOH Drug Formulary Secretariat

Receive application for formulary listing from Oncologist/Clinican\

FORMULARY LISTING PROCESS

• Decision making for formulary listing :

– Evidence-based Approach

• Economic evidence is one of the key elements

considered

• Thus requirement for submission of supporting

documents by proposer to include:

– Evidence on clinical efficacy/effectiveness

– Evidence on safety

– Economic evidence

1. In the absence of economic evidence:

– Cost analysis in comparison to alternatives

currently available is done.

– Calculation of budget implication using estimated

patient population and drug acquisition cost.

2. Critical appraisal of all evidence is conducted. After

appraisal, evidence is selected, synthesised and

presented to the MOH Drug List Review Panel.

3. Feedbacks obtained from relevant Technical Working

Drug Committees also presented

FORMULARY LISTING PROCESS

SUMMARY FOR SELECTION OF MEDICINES

INTO MOH FORMULARY

Decision making for selection of

medicines:

• Based on therapeutic value of

medicine using Evidence-based

Medicine (EBM) Approach

• Tools / Techniques used: Systematic Drug Review

Multi Criteria Decision Analysis

(MCDA): new tool to assist in

formulary decision making,

transparent, explicit decision-making

process. First attempt: HMG-CoA

reductase inhibitors (statins)

• Medicines with added therapeutic

value will be listed in Medicines

Formulary (encompasses the

National Essential Medicines List-

NEML)

WAY FORWARD:

• Review current formulary listing process.

– Proposers of submission will be the

registration holder.

– Submission of local economic studies by

the proposer is encouraged

– Mandatory submission of economic studies

may be a requirement in near future.

• ‘Pharmacoeconomic Guideline for Malaysia’

launched on 31 March 2012 will serve as a

standard for preparation of pharmacoeconomic

studies in Malaysia.

• Plan to develop Centre for Pharmacoeconomics

to facilitate PE research in Malaysia.

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ACCESS TO MEDICINES

NOT LISTED IN MOH FORMULARY

• Access to new innovative medicine is feasible via special mechanism

• Application is approved by Director General of Health

• Approval is given for two categories of oncology medicines:

– registered

– unregistered

• Applications need strong justification :-

-individual patient basis; existing alternatives have been tried; budget availability; cost implication & evidence on efficacy and safety

• Critical Appraisal is done before recommending for approval by Director General of Health

STATISTICS ON SPECIAL APPROVAL (SA)

FOR ONCOLOGY MEDICINES

2012 2013

Registered medicine (%)RM 9,016,094.48

(15.2%)

RM 9,873,077.03

(18.6%)

Unregistered (%)RM 2,852,375.73

(4.8%)

RM 800,348.30

(1.51%)

Total SA expenditure RM 59,202,688.39 RM 52,965,116.08

A) Percentage expenditure on non-formulary oncology medicines

applied via SA over total expenditure for SA medicines

B) Percentage of oncology SA expenditure over total oncology

medicines expenditure:

2012 2013

Total oncology expenditureRM 167,224,314.66

(8.4%)

RM 187,573,860.88

(8.6%)

Total oncology SA

expenditure

RM 11,868,470.21

(7.1%)

RM 10,673,425.33

(5.7%)

POST SPECIAL APPROVAL MONITORING

• Objective:

Obtain more information on effectiveness and

safety of the medicine

• Clinicians to submit patient progress report

every 6 months

• Immediate reporting of ADR if any

Challenges in providing ‘value for

money’ oncology medicines

Variability in Drug Response

• Each patient is different from every other patient due to

uncertainty in response.

• Medicines are approved based on empirical evidence of

efficacy from RCT. Efficacy expressed as average drug

response. Average effects within an RCT population

may be quite different from effects expressed by a

given individual.

Limitations of RCTs in Populations:

Not Always the Gold Standard of Evidence

• Comparability (Internal Validation)

– Assumes a superior treatment (vs placebo) is the best

choice for any given individual in the population

– It could be the wrong drug for many people because of

adverse events

– It could be the best drug for many people who are not at

risk for the adverse event

– Relatively low average responses to many drugs means

non responders receive treatment with no value.

• Generalizability (External Validation)

– Most RCT populations are not representative of patients

who will consume the drug (inclusion/exclusion criteria)

Variability and Uncertainty

• Medicines acting on a cellular target that participates in

the pathogenesis of a disease - Targeted Therapy

• Personalized Medicine – when a biomarker for target

status is used to define a subgroup of patients who have

a different benefit/risk ratio than an unselected

population.

Managed Entry Agreements (MEA)

• From a literature perspective there seems to be a

general agreement that MEAs can, under certain

conditions, help address post licensing uncertainty and

enable early access to innovative treatments

• In general, MEAs offer flexibility in dealing with new and

often expensive technologies, which are characterized

by significant levels of uncertainty

Managed Entry Agreements (MEA)

• Different types of schemes exist in order to address

different needs (budget impact, weaknesses in clinical

evidence, etc.).

• Difficulties to sustain agreements-

Volume based without risk sharing schemes

• Their potential is further amplified by the possibility to

combine financial and non-financial elements in the

same agreement and address different issues at the

same time. e.g. budget impact and use, access and

cost-effectiveness, etc.

Managed Entry Agreements (MEA)

• Agreement including a health-outcome component [e.g.

coverage with evidence (CED) development, payment

for performance]

Collection of information on medicine use and

effectiveness in different sub-groups of patients under

real-life clinical conditions, i.e. outside a clinical trial,

to update treatment guidance, reduce uncertainty and

reach the final reimbursement decision (CED

development).

Need to address quality and safety of unregistered

medicines.

Terminated Patient Assisted Program (PAP) terminated

due to Non Fulfilment of Quantity Requirements

Name of Drug/ Indication Mechanism

Bevacizumab 400mg Injection

[Targeted cancer therapy – breast cancer & colorectal cancer]

3 cycles free for every patient

Everolimus 5mg &

Everolimus 10mg Tablet

[Advanced renal cell carcinoma]

Cost sharing:

- 4 months (MOH), 8 months

(company)

- MOH buys 1 month, bonus 1 month.

- For 4 times purchases (the first 8

months) - given 4 months bonus for

the rest of the year treatment).

Terminated Patient Assisted Program (PAP) terminated

due to Non Fulfilment of Quantity Requirements

Name of Drug/

Indication

Mechanism

Sunitinib12.5mg Capsule[Treatment of GIST after disease progression on or intolerance to ABC & advanced renal

cell carcinoma]

Program started in 2009 as a 3 year pilot for patients in private and public hospitals. Recruitment was by participating physicians and run by an independent third party to maintain patient data privacy . Patients are categorized into different groups. Group 1 - MOH purchase 4 boxes; Group 2 - MOH purchase 8 boxes;Group 3 - MOH purchase 12 boxes;Group 4 - MOH purchase 16 boxes; For all groups, bonuses for the rest of the treatment needed.Program was terminated in 2011 where enrolment was ceased. However, existing patients would still receive the drugs until disease progression ceased.

WHAT IS NEXT FOR NEW INNOVATIVE

ONCOLOGY MEDICINES?

• Value Based Assessment

• Methods review for Highly Specialised

Technologies methods review

• New developments

– Early Access to Medicines

– Adaptive Licensing

• Working with other regulatory & HTA

agencies

CONCLUSION

• As healthcare providers we carry the

responsibility to provide best care within

limited resource setting.

• The current procedures from registration

to post-registration have significant

implications on ensuring the provision of

safe, efficacious/efffective, cost-effective

and quality treatment.

THANK YOU

BETTER HEALTHCARE FOR BETTER FUTURE

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